This invention relates to a method and kit for achieving contraception in gonadal female mammals with GnRH-antagonists without inducing an agonadal state.
Although inhibition of ovulation in the form of estrogen/progestin combination oral contraceptives has been the most effective strategy for achieving reversible pharmacological fertility control in women, because of the known adverse side-effects associated with long term contraception by this method, especially in women who smoke in the 40-44 age group, there is increasing interest in contraception achieved through GnRH analogs that act on the pituitary to induce a hypogonadotropic status. GnRH-agonists do so after a transient stimulatory phase that lasts from 1-3 weeks. Monroe, S. E. et al. Fertil Steril 1985; 43:361; Berquist, C. et al., Contraception, 1979, 19:497. In contrast, GnRH-antagonists lack stimulatory activity, causing prompt reduction of gonadotropin secretion and an agonadal state Kenigsberg, D. et al., Dose-response using a gonadotropin-releasing hormone antagonist. Fertil Steril, 1984, 42:116; Kenigsberg, D. et al., Fertil Steril 1984, 42:116.
As reported by us in J. Clin. Endocrinol. Metab. 62: 734 (April, 1986), the contents of which article are incorporated herein by reference, we have now found that reliably effective contraception (by inhibition of ovulation) can be achieved with GnRH-antagonists in gonadal female mammals without blocking hormonogenesis, thereby avoiding the side effects associated with a long term agonadal state.
For more than a decade, reproductive endocrinologists have sought an adequate strategy to employ GnRH analogs (agonists and antagonists) for contraception in women. Almost uniformly, enthusiasm to move ahead has been thwarted by the knowledge that a persistent functional hypopituitary status, induced by GnRH analogs, is associated with relative ovarian quiescence and a hypoestrogenic milieu. In turn, the expected consequences include hot flushes, urogenital tissue atrophy and bone mineral loss (osteoporosis). Among women of reproductive age this would surely require steroidal replacement therapy (estrogen and progestin), mimicking familiar treatment regiments in postmenopausal women. Indeed, there seems to be little gain in a method based on such complex pharmacology, where the potential consequences of side effects may exceed those of the common oral contraceptives containing similar or the same synthetic steroids. Also, there have been questions about the long-term tolerance to and safety of the GnRH analogs themselves at dosages which achieve an agonadal state.
In accordance with this invention, it is now possible to employ GnRH-antagonists for reliable ovulation inhibition, while avoiding frank estrogen deficiency and relying on natural ovarian steroids to maintain normal metabolic homeostasis.